The proposed studies are focussed on further delineation between biologically active chemical species of Ga, In or As and early biological indicators of target cell injury. These studies will involve in vivo exposure of rats and hamsters to intratracheal instillations and intraperitoneal injections of Ga, In As, GaAs, or InAs. Target tissue concentrations of these elements will be fractioned into inorganic, macromolecular and organelle components using a variety of analytical and biochemical methodologies. These data will be correlated with metal or mixture-specific biochemical responses involving perturbations of heme biosynthetic pathway enzyme activities in order to delineate mechanisms, sensitivity and specificity of alterations in the pathway by these elements on an individual or mixture basis in blood, liver and kidney. These data will be quantitatively correlated with ultrastructural morphometric analyses of blood, liver cells and renal proximal tubule cells in situ and tissue heme biosynthetic pathway enzymes in order to delineate which of these indicator classes is the best indicator for cell injury form chemical species of Ga, In or As either alone or in mixture combinations. In order to further delineate mechanistic relationships between intracellular chemical species of these elements, the biological indicators and mechanisms of cell injury, in vitro studies using red blood cells and primary hepatocyte and renal tubule epithelial cell cultures will be conducted during the second phase of the project. These studies will be conducted using stable soluble chemical forms of Ga, In and As. Results of these studies should yield new insights into the necessary relationships between specific intracellular chemical species of Ga, In or As, early metal-specific biochemical responses to these agents and novel biological indicators of target cell injury following acute intratracheal instillation of particulates of these elements, either alone or in combination.